Pathway Selection of Radiation Response by Regulation of Epigenomic Modification

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K12178
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: National Institutes for Quantum Science and Technology
• Principal Investigator: Nakajima Nakako 国立研究開発法人量子科学技術研究開発機構, 量子生命・医学部門量子医科学研究所, 研究員 (50402863)
• Co-Investigator(Kenkyū-buntansha): 浦 聖恵 千葉大学, 大学院理学研究院, 教授 (80289363)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: がん治療 / DNA修復 / エピジェネティクス / ヒストン修飾酵素 / DNA損傷応答

Outline of Final Research Achievements

The DNA repair pathway that determines radiosensitivity is affected not only by DNA repair factors, but also by the chromatin structure of the DNA damaged area.In this study, to assess the molecular mechanism of the histone-modifying enzyme H3K36 methylase NSD2 that regulates chromatin structure in DNA damage response, NSD2-deficient cells were created and their effects on DNA damage responses were analyzed. NSD2 deficiency did not affect survival or growth suppression against X-rays. NSD2-deficient cells were more susceptible to DNA-damaging anticancer drugs and ultraviolet irradiation. Expression of the protein SLFN11, which enhances the effects of anticancer drugs, was increased in NSD2-deficient cells. These results suggest that NSD2 regulates DNA damage-induced cell death by regulating SLFN11 expression.

Free Research Field

放射線・化学物質影響科学

Academic Significance and Societal Importance of the Research Achievements

ヒストンH3K36メチル化は転写活性のあるゲノム領域に集積するヒストン修飾であるにも関わらず、単にヒストンH3K36メチル化酵素を欠損させても遺伝子発現に顕著な変化が認められず、機能が判然としないエピゲノム修飾であった。本研究は遺伝子発現解析を通してヒストンH3K36メチル化酵素を介した新たな放射線応答制御の発見である。また、ヒストンH3K36メチル化酵素遺伝子の変異はがん細胞においてしばしば見出されており、本研究によってエピゲノム制御異常による細胞がん化の仕組みが明らかになり、分子標的薬の重要な基盤となると期待される。